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• The Fanconi Anemia-BRCA Pathway and Chemosensitivity of Human Cancer
• Identification of an Immunologic Signature of Ovarian Cancer for Use as an Early Cancer Screen
• A Phase II Trial of Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) with Weekly
PROTEIN Bound Paclitaxel (Abraxane™) as Chemoimmunotherapy for Relapsed, Platinum-
Resistant Epithelial Ovarian Cancer
• Endometrial Hyperplasia Outcomes—A Cohort Study
• Genetic and Epigenetic Markers in Ovarian Cancer (K08)
The Fanconi Anemia-BRCA Pathway and Chemosensitivity of Human Cancer
Elizabeth M Swisher, MD
One of the most difficult problems in the treatment of cancer is acquired resistance to chemotherapy. Defects in DNA repair are likely to play a critical role in the sensitivity of cancer cells to chemotherapeutic drugs, many of which are DNA-damaging agents.
Fanconi Anemia (FA) is a genetic disorder characterized by cancer susceptibility and cellular hypersensitivity to DNA crosslinking agents, such as cisplatin and melphalan. FA proteins and breast/ovarian cancer susceptibility gene products (BRCA1 and BRCA2) cooperate in a common DNA damage-activated signalling pathway (the FA-BRCA pathway), which controls DNA repair. We hypothesize that interity of the FA-BRCA pathway is a critical determinant of resistance of tumor cells to chemotherapy with DNA crosslinking agents.
The goals of our proposed research are 1) to elucidate the role of the FA-BRCA pathway in cisplatin sensitivity/resistance of cancer cells, 2) to determine if the sensitivity of tumor cells to DNA crosslinking agenst can be increased by modulating the FA-BRCA pathway using small molecule inhibitors of the pathway, and 3) to further elucidate the mechanism of regulation of the FA-BRCA pathway. We plan to determine the role of one of the FA genes, BRCA2/FANCD1, in acquired resistance to cisplatin using two BRCA2-deficient cell lines we recently identified.
Funding Source: Fred Hutchinson Cancer Research Center (FHCRC)
Contact: Elizabeth M Swisher, MD, (206) 685-2463
Ends 6/30/12
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Identification of an Immunologic Signature of Ovarian Cancer for Use as an Early Cancer Screen
Heidi J Gray, MD
The goal of this proposal is to develop a serum-based assay that evaluates the use of antibody immunity as a diagnostic tool for early detection of ovarian cancer. There is ample evidence in the literature demonstrating the immunogenicity of ovarian cancer. Previous work has described several tumor-associated antigens and has shown patients have an ability to mount a T cell response to these antigens. It is well documented that evidence of exposure to tumor antigens exists by assaying for antibodies to tumor -associated antigens (TAAs). Evidence of this antibody response has been shown to occur early in tumorigenesis and therefore has potential for use as an early detection screen.
The work proposed here will identify the immunologic signature of ovarian cancer composed of a panel of serum antibodies. The study will be done using serum samples from ovarian cancer patients and age-matched volunteer donors. The samples will be analyzed using a high-throughput technique that combines the use of a phage display library and protein array. This technique makes it possible to evaluate hundreds of phage-expressed proteins simultaneously to identify those that define the immunologic signature associated with ovarian cancer.
The results of this study will provide data on the feasibility of multi-parametric immune-based assays in discriminating patients with cancer from non-tumor bearing individuals and provide the basis for a definitive application validating the approach.
Funding Source: Ovarian Cancer Research Fund (OCRF)
Contact: Heidi J Gray, MD, (206) 685-2463
Ends 12/31/10
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A Phase II Trial of Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) with Weekly PROTEIN Bound Paclitaxel (Abraxane™) as Chemoimmunotherapy for Relapsed, Platinum-Resistant Epithelial Ovarian Cancer
Ron E Swensen, MD
Abraxis Bioscienc is providing Abraxane™ for use in the clinical trial titled “A Phase II Trial of Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) with Weekly Protein Bound Paclitaxel (Abraxane™) as Chemoimmunotherapy for Relapsed, Platinum-Resistant Epithelial Ovarian Cancer.”
The Clinical trial is sponsored by Berlex under a separate contract. The study drug will be provided free of charge to the University of Washington by Abraxis Bioscience for the purpose of this trial.
Funding Source: Berlex
Contact: Ron E Swensen, MD, (206) 543-3669
Ends 12/31/08
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Endometrial Hyperplasia Outcomes—A Cohort Study
Susan D Reed, MD, MPH
Endometrial hyperplasia is a precancerous lesion of the uterine lining manifested as an overgrowth of the glandular endometrium. At least three types of hyperplasia, with presumed increasing severity, have been described: simple, complex, and hyperplasia with atypia. The two most severe types, complex hyperplasia and hyperplasia with atypia are generally treated with either a progestin or by hysterectomy, depending on the disease severity, desire for conservative therapy and preservation of childbearing potential.
The purpose of this 4-year, cohort study is to investigate the efficacy of progestin treatment for the most severe forms of endometrial hyperplasia. Current predictions of the likelihood of response or progression are based on data from small studies lacking controls and are not coupled with standardized pathology studies, and so at present, we have little scientific basis for helping women to choose between hysterectomy, progestin therapy or expectant management.
Our specific aim is to compare the rates of persistence or progression of endometrial hyperplasia among women not treated with progestin to that of women treated with a progestin in 2 groups with:
- Complex hyperplasia, and
- Hyperplasia with atypia
Our secondary aim is to explore the association of pathologic markers among women with the more severe forms of endometrial hyperplasia as predictors of persistence and progression of disease.
Funding Source: Fred Hutchinson Cancer Research Center (flow through from NIH)
Contact: Susan D Reed, MD, MPH, (206) 744-4292
Ends 12/31/08
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Genetic and Epigenetic Markers in Ovarian Cancer (K08)
Elizabeth M Swisher, MD
The candidate is a gynecologic oncologist with a commitment to a career in basic science and translational research. The University of Washington has a strong clinical cancer program, an established gynecologic cancer tissue bank, and a renowned research program in genomics and medical genetics. Under the guidance of Mary-Claire King, PhD, the candidate will use these institutional resources to gain advanced training in genetics laboratory research while completing the proposed project. She will participate in the didactic activities for fellows in the Division of Medical Genetics.
Ovarian cancer has the highest mortality among gynecologic cancers, and current screening strategies are inadequate for application to the general population. This study is based on the hypothesis that DNA from ovarian cancers is shed into the peritoneal cavity and bloodstream and can be exploited as a diagnostic marker.
This project has three specific aims:
- Identify differences in mitochondrial DNA (mtDNA) sequences in ovarian cancers by comparing tumor to matched normal DNA from the same patients. Determine whether mtDNA sequences characteristic of tumors can be detected in peritoneal fluid or plasma from ovarian cancer patients.
- Identify somatic p53 mutations in ovarian cancers. Determine whether mutant p53 sequences can be detected in peritoneal fluid or plasma from ovarian cancer patients.
- Identify promoter methylation patterns of genes in ovarian cancers, including BRCA1, MLH1, HIC1, MINT25, MINT31, and RASSF1A. Determine whether tumor-specific methylated DNA can be detected in peritoneal fluid or plasma from ovarian cancer patients.
The candidate will evaluate three different types of molecular alterations, variants in mitochondrial DNA sequence, somatic mutations in p53, and promoter methylation that reveal the presence of tumor DNA in body fluids of women with ovarian cancer. She will correlate identification of tumor DNA in plasma or peritoneal fluid with clinical status and outcome to determine whether tumor DNA in body fluids is a sensitive marker of disease.
Major Goals: To assess—
- the likelihood of histologic persistence or progression of endometrial hyperplasia; and
- the rate of subsequent hysterectomy or endometrial cancer among women with complex hyperplasia or hyperplasia with atypia.
Funding Source: NIH
Contact: Elizabeth M Swisher, MD, (206) 685-2463
Ends 8/31/08
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